Prostate cancer (PCa) is a leading cause of cancer death in men and diagnosed cases steadily increase. In the U.S., approximately 198,000 men will be diagnosed and 32,000 will die this year. Therefore, identification of causative genes and molecular pathways underlying prostate tumor initiation, growth and metastatic spread represents an urgent priority for the rationale development of improved diagnostics and preventative and therapeutic strategies. We demonstrated that the tumor suppressor KLF6, a member of the Kruppel-like family of zinc finger transcription factors which regulate growth-related signal transduction pathways, is frequently inactivated in human PCa. Two lines of evidence now suggest that KLF6 status can both define PCa susceptibility and long-term outcome. First, in a multi-institutional study of over 3,400 men, we have shown that a specific germline KLF6 SNP, regardless of family history of disease, increases lifetime risk of PCa. This SNP increases KLF6 gene alternative splicing to yield a biologically active, growth- promoting isoform, KLF6-SV1, that increases tumor cell proliferation, invasion, and in vivo tumor growth. Second, multiple gene expression studies link decreased KLF6 expression with tumor recurrence, poor clinical outcomes and chemotherapeutic resistance. Therefore, the hypothesis of this proposal is that loss of wild type KLF6 and/or increased expression of its alternatively spliced isoform KLF6-SV1, play a central role in the spectrum of PCa development, progression and metastasis. Our goals are to identify the clinicopathologic impact of KLF6 and KLF6-SV1 dysregulation on tumor behaviour and through genetically engineered in vivo models, identify the genetic and proteomic mechanisms underlying these biologic effects on PCa. Therefore, the specific aims of this proposal are: (1) Define the prevalence and clinicopathologic effects of altered KLF6 and KLF6-SV1 expression in PCa development and progression;(2) Investigate the effects of targeted KLF6 and KLF6-SV1 manipulation on prostate development, tumor susceptibility and malignant transformation, and;(3) Define the "KLF6-PCa interactome" - KLF6 and KLF6-SV1 protein-protein interactions critical to tumorigenesis and metastasis.